Natural history and progression of atherosclerotic renal vascular stenosis

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1 NEPHROLOGY 2010; 15, S204 S209 doi: /j x Natural history and progression of atherosclerotic renal vascular stenosis Date written: December 2008nep_1242 Final submission: October 2009 Authors: Subramanian Karthik Kumar, Robert MacGinley, Murty Mantha, Peter Mount, Matthew Roberts, George Mangos [Correction added after online publication on 1 April 2010: Authors names added.] GUIDELINES No recommendations possible based on Level I or II evidence SUGGESTIONS FOR CLINICAL CARE (Suggestions are based on Level III and IV evidence) Atherosclerotic renovascular stenosis is a potentially progressive disease. Risk factors for progressive stenosis and renal artery occlusion include: uncontrolled systolic hypertension (>160 mmhg) diabetes mellitus high grade (>70%) ipsilateral and contralateral atherosclerotic renal vascular disease (ARVD), and significant baseline proteinuria. Risk factors for atrophy include: systolic hypertension (>160 mmhg) stenosis of more than 60%, and decreased renal cortical blood flow. Risk factors for decline in glomerular filtration rate (GFR) include: abnormal baseline creatinine (>128 mmol/l) bilateral ARVD or ARVD in solitary kidney. Atherosclerotic renovascular stenosis is associated with high mortality and morbidity due to atherosclerosis elsewhere, particularly coronary artery disease. IMPLEMENTATION AND AUDIT Not relevant to this subtopic. BACKGROUND This guideline covers the following areas: ARVD renal artery stenosis (RAS) without surgical and endovascular intervention RAS with or without medical management. For the purposes of this guideline and after accommodating for variability between studies (reviewed below), ARVD has been classified into the following grades based on the degree of stenosis: 2010 The Authors Journal compilation 2010 Asian Pacific Society of Nephrology high (>70%) intermediate (50 70%), and low grade (<50%). The following endpoints have been addressed when considering the natural history of ARVD: Clinical: requirement of hypertensive medications Laboratory: change in GFR Ultrasound: change in kidney sizes Angiographic/duplex sonography: progression of stenosis, and Other vascular comorbid events: stroke, coronary events. Approximately 1 6% of hypertensive patients have renovascular lesions on arteriography. 1 4 Unselected autopsy data suggest that 27% of patients over 50 years have more than 50% stenosis of at least one renal artery. 5 It is the primary cause of renal failure in 5 22% of patients over 50 years who begin dialysis. Various risk factors have been identified in relation to the occurrence and progression of ARVD. Management of ARVD is made controversial by the lack of randomized controlled trials. Available studies differ widely in the variables that may influence renal survival such as hypertension control, interventions for revascularization (surgery, angioplasty alone, and angioplasty with stenting with and without distal protection devices) and medical therapy. Furthermore, the potential risks of the intervention such as contrast nephropathy and cholesterol embolism may cause significant morbidity. Knowledge of the natural history and risk factors for progression of RAS can thus be helpful in deciding whether, when and how to intervene. A number of studies looking at the natural history of ARVD have demonstrated progression of RAS, including to renal artery occlusion. However, there is no Level I or II evidence to support any recommendations regarding the natural history. Prospective studies are scarce because of the multiple interventions that either confound the results or make such study designs impractical. Allocation of patients with very mild or very severe lesions to the conservative management arm may lead to selection bias. Knowledge of the natural progression of ARVD has been largely derived

2 Renovascular Disease S205 from studies that are retrospective, have used historical controls, or case series. Moreover, imaging to determine progression has been initiated by clinical factors rather than being driven by a study protocol, and various imaging modalities have been used. Finally, many of the studies were performed before modern treatment of risk factors for atherosclerotic cardiovascular disease with drugs such as statins and renin-angiotensin system antagonists were available. These guidelines focus on ARVD as this is the most common type of RAS and the treatment of this cohort is most contentious. Fibromuscular dysplasia (FMD) is not specifically addressed by this guideline. FMD has at least five different types with varied rates of progression and it is not currently possible on the basis of angiography to classify lesions to a particular FMD subtype. Furthermore, FMD is usually associated with hypertension and interventional therapy is unequivocally favoured irrespective of the subtype. SEARCH STRATEGY Databases searched: The terms used to define atherosclerotic renovascular disease were renal artery obstruction (as a MeSH term and text word) and renal artery stenosis, renovascular disease$ and renal artery occlusion$ as text words. To define this further, the terms atherosclerosis and arteriosclerosis, as both MeSH terms and text words were searched. MeSH terms and text words for natural history and progression were combined with MeSH terms and text words for atherosclerotic renovascular disease. The search was performed in Medline (1950 April 2009). In addition, the reference lists of manuscripts retrieved by the above method were manually reviewed for additional studies. The Cochrane Renal Group Trials Register was also searched for trials not indexed in Medline. Date of searches: 2 April WHAT IS THE EVIDENCE? The following text summarizes the studies identified by the literature search. Table 1 in the Appendix presents a brief description of the studies. Progression of stenosis Qualitative data have been reviewed from prospective studies that recruited patients with varying degrees of stenoses to assess the variation in the rates of disease progression in patients with different grades of stenoses. Arteriographic studies A number of studies have performed follow-up renal angiograms in patients to examine the progression of lesions. These are predominantly older studies with small sample sizes. The first observational evidence for the progressive nature of ARVD came in 1966 from Dustan and co-workers. Using urographic and angiographic studies, they demonstrated that 61% of 18 patients progressed over a 6-year period. 6 In 1968, Meaney et al. reported angiographic follow-up results for 39 patients with ARVD (36 with ARVD and 3 with both ARVD and FMD). Of these patients, 14 were noted to have progressive disease over the period of follow up of 7 years with 7 patients showing progression within 2 years and 3 patients within 1 year. 7 Wollenweber et al. in 1968 reported a study involving 30 patients with a mean age of 52.7 years for females and 54.5 years for males. Patients with hypertension and/ or azotemia were selected for the study. After an initial aorto-renal arteriogram they were followed up with a second study after a mean interval of 28.1 months. A worsening of stenosis was reported in the renal artery to one kidney in 13 patients and in arteries to both kidneys in 6 patients. 8 In a study by Schreiber et al. 44% of 85 patients had progression of ARVD on mean follow up of 52 months. A total of 16% progressed to total occlusion. Half the patients with less than 50% stenosis demonstrated no change in the sequential angiogram. The rate of progression to complete occlusion was 39% in the 75 99% stenosis group compared with 5% in the <50% group. The average monthly rate of progression in the three patient groups (<50%, 50 75%, 75 99%) were 1.59, 1.37 and 2.01, respectively. 9 Dean et al. performed a subset analysis of a prospective randomized study and reported progression in patients designated to the medical management arm. The method of randomization was not specified. Over a mean follow-up period of 28 months, progression to total occlusion occurred in four patients (12%). No data were provided regarding the baseline degree of stenosis in these arteries. 10 Renal duplex sonography studies Renal duplex sonography (RDS), although fraught with drawbacks of reproducibility and availability of technical expertise, is currently considered a useful tool for monitoring ARVD when optimal sonographic conditions can be ensured. A number of studies have looked at the stenosis progression with RDS. A large prospective observational study by Caps et al. looked at 295 renal arteries in 170 patients over a 5-year period using RDS. They used the principle that blood flow velocity across the stenosis was proportional to the degree of vessel diameter reduction. An increase in peak systolic velocity (PSV) of 3100 cm/s was derived as being significant based on the between-observer variability for renal artery PSV measurements. Disease progression was defined as any detectable increase in the degree diameter reduction in the renal artery, including renal artery occlusion. The 3-year cumulative incidence of renal artery disease progression was 18%, 28% and 49% for renal arteries initially classified as normal, <60% stenosis and 360% stenosis, respectively. Systolic blood pressure (BP) mmhg, diabetes mellitus, ipsilateral or contralateral stenosis 3 60%, and occlusion of contralateral renal artery were identified as independent risk

3 S206 The CARI Guidelines factors for stenosis progression in a stepwise Cox proportional hazard analysis. 11 Study limitations, apart from being observational included: selected patients had hypertension or reduced kidney function. Patients with ARVD and normal BP and renal function were not included. use of ultrasound as a tool to follow up has its limitations. These include the potential for variability introduced by inter-observer variability when multiple sites and technicians are involved, and test retest reproducibility. inadequate power to detect the influence of other wellknown risk factors for atherosclerosis disease progression such as lipid profiles, race and renal function, and no data on the use of important medical therapies such as inhibitors of the renin-angiotensin system or statins. Despite these limitations, this study provides insight into the risk factors associated with the progression of stenosis. The first population-based prospective study looking at incident RAS and its progression was reported by Pearce et al. in RDS was applied to a selected geographic cohort of elderly patients (mean age years) participating in the Cardiovascular Health Study, an observational population-based study for cardiovascular disease and stroke risk factors. The study included all free-living persons in each sampled household aged 3 65 years. Among the 834 participants, a RAS of 360% was identified in 6.8% (57/834) of participants. There was a significant association with increasing participant age, decreased HDL and increased systolic BP. After an 8-year period, 119 participants had a second RDS, which was technically satisfactory in 235 kidneys. At first examination, ARVD was present in 13 kidneys (5.5%). None of the subjects who had > 60% stenosis at baseline progressed to occlusion at the second study. New stenoses of 360% ( incident stenoses) were identified in 9 kidneys (2.9%). By univariate analysis, the increase in diastolic BP (P = 0.01) and decrease in renal size (P < 0.001) were significantly associated with incident stenoses. A healthy cohort effect from healthy participants and significantly less participant re-recruitment at follow up was collectively considered to have led to an underestimation of RAS progression. The criteria for progression was change in PSV of greater than twice the standard deviation of the predicted change in an age-matched cohort over a median follow-up period of 2 years. In the control group, 95% had some of the recognized risk factors for atherosclerosis. This could have resulted in a control cohort with a higher than expected rate of progression resulting in an underestimation of the progression in the study cohort. Other notable sources of bias were technological improvements in RDS using colour flow Doppler technology at the second follow up, inter-observer differences in reporting and a loss to follow up, with only a small number of patients who participated in the second study. Of the participants, 224 died after the initial study. There were little data on the cause of death, which was presumed by the authors to be mostly from cardiovascular causes. This could have selected participants with less severe vascular disease to complete the follow-up duplex, thus underestimating the progression rate. Renal atrophy A number of studies suggest that ARVD can cause renal atrophy, and some risk factors for this have been identified. Renal duplex sonography studies Caps et al. in their stenosis progression study discussed above examined the risk factors and rate of atrophy of kidneys with a 360% stenosis on RDS. 13 A total of 204 kidneys with such stenoses in 122 participants were followed for a mean of 33 months (range 5 72 months). They excluded kidneys with renal artery occlusion and prior intervention to their arteries as well as those with renal sizes < 8.5 cm. The baseline lengths were close to those expected in an age- and sex-matched population. A reduction of renal length greater than 1 cm occurred in 16.2% of the kidneys. The cumulative incidence of atrophy at 2 years was 5.5% for kidneys with normal baseline renal arteries, 11.7% in the 260% stenosis group and 20.8% in the 360% group. This association was significant (P = 0.009). Those arteries that occluded during the study period had 360% stenosis at baseline and these kidneys shrank 31 cm on follow up. The three baseline factors independently associated with renal atrophy (identified by the univariate Cox proportional analysis) were systolic hypertension, severity of RAS and diminished renal cortical blood flow velocity. A 1.9-fold and 1.6-fold increase in the risk of renal atrophy was associated with every 20 mmhg increase in systolic BP and 10 mmhg increase in diastolic BP, respectively, at the follow-up examinations. The use of ACE inhibitors at baseline showed no significant association with renal atrophy even in kidneys with significant stenosis. There was no significant association between the presence of accessory renal arteries and a decreased risk of atrophy. Finally, the mean change in serum creatinine concentration was +7 mmol/l per year and +29 mmol/l per year in participants with atrophy detected in one kidney and both kidneys, respectively. Arteriographic studies In an observational series of patients with ARVD using intravenous pyelography, Dean et al. demonstrated a stability (<5% reduction) in renal sizes in 37% of patients, mild to moderate decrease (5 9%) in 26% of patients and significant (>10%) reduction in kidney length (equated to 30% decrease in renal mass) in 37% of patients. 10 This study supports the hypothesis that ARVD could be associated with progressive renal atrophy. However, there was little data relating renal atrophy to degree of baseline stenosis. The study by Schreiber et al. used angiographic images for kidney sizes and reported a reduction in renal size in 70% of patients with progressive ARVD compared with 13% in those with stable stenosis (P < 0.001). However, there is little information about the side of the stenosis, the side of renal atrophy and correlation between them. 9

4 Renovascular Disease S207 Renal function A number of longitudinal studies have demonstrated a decline in kidney function over time in patients with ARVD. Schreiber et al. reported change in serum creatinine in different categories of baseline stenosis (<50%, 50 75%, 75 99% and 100%) over a mean follow-up period of 52 months. An increase in serum creatinine levels was seen in 54% of patients with progressive disease (defined as change from one category of stenosis to a category of higher grade stenosis), while an increase was observed in only 25% of patients without evidence of angiographic progression. 9 However, these data are limited by the use of serum creatinine, which is a poor indicator of individual kidney function as a marker of renal function. Chabova et al. in a retrospective cohort study at the Mayo Clinic, looked at 68 patients with angiographically proven high-grade stenosis (>70%) over a mean period of 38.9 months. Serum creatinine rose from 124 mmol/l to 176 mmol/l for the entire group. This result was skewed by 10 patients (14.7%), 6 of whom developed end-stage kidney disease. Among patients with bilateral high grade stenosis and with unilateral high grade stenosis to a solitary functioning kidney, 20% showed a rise in serum creatinine over an average follow up of 36.4 months while 12.8% of patients with unilateral high grade stenosis had a rise in serum creatinine over an average follow-up period of 40.1 months. 14 Stenosis to the entire renal mass was found to be associated with higher baseline creatinine and greater likelihood of clinical deterioration. In a cross-sectional study involving a cohort of patients from the Cardiovascular Health Study, Edwards et al. analysed the association between ARVD and excretory renal insufficiency. 15 The presence of ARVD showed an association with renal insufficiency (odds ratio 2.21; 95% confidence interval: ; P = 0.043) that was independent of effects of age, race, sex, body weight and diabetic status. The prospective multicentre observational study by Pillay et al. in 2002 recruited patients with a >50% RAS from patients undergoing angiography for peripheral vascular disease. A total of 159 renal arteries in 85 patients with such stenoses were followed up by renal ultrasound over a mean period of 30 months. Renal length and BP were stable. A significant increase in serum creatinine was noted in the survivors of unilateral disease without intervention. 16 The finding of declining renal function in patients with unilateral ARVD suggests that intrinsic parenchymal disease, rather than the disease of the large renal arteries is the major determinant of declining renal function in this population. This hypothesis was supported by an elegant prospective study by Farmer et al. that looked at the relationship between presence of RAS and single kidney glomerular filtration rate (SK-GFR) using radionuclide studies in 79 patients with ARVD. The study noted a similar impairment of renal function in kidneys with and without ARVD while kidneys with occluded renal arteries were associated with significant reduction in function compared with the contralateral kidney. It was concluded that unilateral ARVD could not only compromise ipsilateral SK-GFR by ischemic mechanisms but also contralateral SK-GFR by nonischemic mechanisms. 17 The study by Losito et al. reported on 195 patients with ARVD over an average follow up of 54 months. 18 Of the total, 54 were maintained on medical management, with 38.8% on an ACE inhibitor as one of the many antihypertensives in the medical treatment arm. During the period of follow up, the mean change in creatinine in the medically treated arm was an increase of 108 mmol/l. When worsening renal function was examined by Losito et al. two factors were found to be significant by multivariate analysis. The first was an abnormal baseline creatinine (>128 mmol/l) with a hazard ratio of The second was the use of an ACE inhibitor which was associated with a reduced risk of further impairment of renal function (hazard ratio of 0.29), more pronounced in the medically treated arm. Of note, was the significant proportion of patients (17 out of 54) in the medical arm who were using statins. 18 Hypertension There are only a few studies that have looked at the changes in number and need for antihypertensive medications in patients with ARVD over time. In most of the studies, there is little information on maximizing the dose of a particular drug before resorting to a second drug. In the Chabova et al. study, by design all of the patients were hypertensive and had a mean BP of 157/83 mmhg while on antihypertensive therapy. 15 During the follow up, the average requirement for antihypertensive medications rose significantly from (P = 0.02) per person. There was a non-significant trend towards lower systolic and diastolic BP. Only 32.4% of the patients were taking an ACE inhibitor and the proportion of patients taking each class of antihypertensive medication did not differ significantly at the end of the follow-up period. Other vascular bed involvement and related comorbid events Wollenweber et al. reported clinical evidence of associated symptomatic coronary disease or cerebrovascular disease in 31% of patients with mild to moderate RAS and 49% of patients with marked or severe RAS. New symptomatic cardiovascular disease including cardiac failure developed in 47% of patients within 5 years. 8 This study looked at a relatively young cohort of atherosclerotic patients and the patients selected for medical treatment had a milder degree of stenosis. There were no data on the type and number of antihypertensive medications or BP control. The estimated 5-year survival rate was 66.7% in patients with ARVD compared with 91% in the comparable normal population. No significant difference in survival was noted between the medical and the surgically treated group despite the more severe atherosclerotic disease in the surgical group.

5 S208 The CARI Guidelines The elderly cohort of patients (mean age 71.8 years) in the study by Chabova et al. showed higher mortality in patients with bilateral stenosis when compared with those with unilateral disease (42% vs 21.3 %; P = 0.07). Disease was identified in other vascular beds in 97.1% of patients. 14 SUMMARY OF THE EVIDENCE Atherosclerotic renal vascular disease is a progressive disease, with high grade stenosis (>60%), systolic hypertension (>160 mmhg) and diabetes associated with faster progression. Abnormal baseline creatinine and bilateral stenosis are associated with greater likelihood of deterioration of renal function. Patients with ARVD have increased mortality and morbidity, particularly from cardiovascular disease. WHAT DO THE OTHER GUIDELINES SAY? Kidney Disease Outcomes Quality Initiative: No recommendation. UK Renal Association: No recommendation. Canadian Society of Nephrology: No recommendation. European Best Practice Guidelines: No recommendation. International Guidelines: No recommendation. SUGGESTIONS FOR FUTURE RESEARCH 1. Perform a large prospective study with ultrasound surveillance to look at risk factors for progression. 2. Investigate the variability in progression rate when different imaging modalities are used for follow up. 3. Investigate the influence of lifestyle changes, statins, renin-angiotensin system blockade alone or in combination on stenosis progression. CONFLICT OF INTEREST Subramanian Karthik Kumar has no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by CARI. REFERENCES 1. Correa RJ Jr, Conway J, Hoobler SW et al. Renal-vascular disease as a cause of hypertension: Selection of patients for aortographic studies. J. Mich. State Med. Soc. 1962; 61: Yamauchi H. Screening hypertensive patients for surgically reversible causes unsettled issues. Heart Lung 1981; 10: Berglund G, Andersson O, Wilhelmson L. Prevalence of primary and secondary hypertension: Studies in a random population sample. BMJ 1976; 2: Rudnick KV, Sackett DL, Hirst S et al. Hypertension in a family practice. Can. Med. Assoc. J. 1977; 117: Rimmer JM, Gennari J. Atherosclerotic renovascular disease and progressive renal failure. Ann. Intern. Med. 1993; 118: Dustan HP, Meaney TF, Page IH. Comparative treatment of renovascular hypertension. In: Gross F (ed.) Antihypertensive Therapy. New York: Springer-Verlag, 1966; Meaney TF, Dustan HP, McCormack LJ. Natural history of renal artery disease. Radiology 1968; 91: Wollenweber J, Sheps SG, Davis GD. Clinical course of atherosclerotic renovascular disease. Am. J. Cardiol. 1968; 21: Schreiber MJ, Pohl MA, Novick AC. The natural history of atherosclerotic and fibrous renal artery disease. Urol. Clin. North Am. 1984; 11: Dean RH, Kieffer RW, Smith BM et al. Renovascular hypertension: Anatomic and renal function changes during drug therapy. Arch. Surg. 1981; 116: Caps MT, Perissinotto C, Zierler RE et al. Prospective study of atherosclerotic disease progression in the renal artery. Circulation 1998; 98: Pearce JD, Craven BL, Craven TE et al. Progression of atherosclerotic renovascular disease: A prospective population-based study. J. Vasc. Surg. 2006; 44: Caps MT, Zierler RE, Polissar NL et al. Risk of atrophy in kidneys with atherosclerotic renal artery stenosis. Kidney Int. 1998; 53: Chabova V, Schirger A, Stanson AW et al. Outcomes of atherosclerotic renal artery stenosis managed without revascularization. Mayo. Clin. Proc. 2000; 75: Edwards MS, Hansen KJ, Craven TE et al. Relationships between renovascular disease, blood pressure, and renal function in the elderly: A population-based study. Am. J. Kidney Dis. 2003; 41: Pillay WR, Kan YM, Crinnion JN et al. Prospective multicentre study of the natural history of atherosclerotic renal artery stenosis in patients with peripheral vascular disease. Br. J. Surg. 2002; 89: Farmer CK, Cook GJ, Blake GM et al. Individual kidney function in atherosclerotic nephropathy is not related to the presence of renal artery stenosis. Nephrol. Dial. Transplant. 1999; 14: Losito A, Errico R, Santirosi P et al. Long-term follow-up of atherosclerotic renovascular disease. Beneficial effect of ACE inhibition. Nephrol. Dial. Transplant. 2005; 20:

6 Renovascular Disease S209 APPENDIX Table 1 Characteristics of included studies Study Patients (arteries) Age (years) Study design Setting Participants Control Follow up Results Meaney et al 91, 39 ARVD Observational, (1968) 7 serial angiograms Wollenweber (range: Observational, et al (1968) ) serial arteriograms Schreiber et al Retrospective (1984) 9 review Dean et al (mean (1981) 10 age unspecified) Caps et al 170 individuals, (1998) renal arteries Prospective randomized (method of randomization not specified) Prospective observational Pearce et al 13 renal arteries 81.9 Population-based (2006) 12 prospective Chabova et al 68 patients 71.8 Retrospective (2000) 14 cohort Cleveland clinic Aortico renal arteriograms hospital performed for hypertension +/ uremia between Mayo clinic Patients with ARVD who had serial angiograms Cleveland clinic Renovascular hypertension from ARVD randomized to medical management Vanderbilt University Medical Centre University of Washington Wake Forest University School of Medicine Edwards et al 834 individuals 77.2 Case control Wake Forest (2003) 15 University School of Medicine Pillay et al 159 renal arteries 71 Prospective Joint vascular (2002) 16 (in 85 patients) multicentre research group, UK observational Farmer et al 79 patients 68.9 Prospective (1999) 17 descriptive Subjects with 31 stenotic main renal artery in RDS Selected geographic cohort of elderly patients (mean age years) participating in the Cardiovascular Health Study Angiographically proven high grade stenosis (>70%) 6 months 7 years Of the 39 patients, 14 showed progressive disease. Mean: 28.1 months 52 months 44% progressed to complete occlusion (39% in the 75 99% stenosis group and 5% in the <50% group). 28 months 12% progressed to total occlusion, 17% exhibited contralateral ARVD progression. 33 months The 3 years cumulative incidence of stenosis progression was 18%, 28% and 49% for renal arteries initially classified as normal, <60% stenosis, and 360% stenosis, respectively. 8 years None with >60% stenosis progressed to complete occlusion. Incident ARVD occurred in 2.9% of the study population. Mayo clinic Cardiovascular Health Study 38.9 months Stenosis to the entire renal mass was associated with higher baseline creatinine and greater likelihood of clinical deterioration. Guy s and St Thomas renal unit Losito et al 54 patients 65.6 Observational Radiology Institute (2005) 18 of the University of Perugia, Italy ARVD, atherosclerotic renal vascular disease; RDS, renal duplex sonography. Patients with peripheral arterial disease with incidentally picked up ARVD (>50% stenosis) Subjects without ARVD Presence of ARVD showed an association with renal insufficiency (odds ratio 2.21). Angiographically proven ARVD 30 months Significant increase in creatinine in patients with unilateral ARVD. Patients in the medical treatment arm 25 months Similar impairment of renal function in kidneys with and without ARVD. Kidneys with occluded renal arteries were associated with significant reduction in function compared with the contralateral kidney months Mean change in serum creatinine in the medically treated arm was +108 mmol/l.